Bioengineering patterning in complex tissues to uncover how mechanochemical feedback drives morphological development

First supervisor: Dr Alberto Elosegui-Artola

Second supervisor: Dr Zena Hadjivasilou

A funded PhD project from the King’s College London Multiscale Models for Life (MM4L) Centre for Doctoral Training.

Duration and details of award: 3.5 years including a stipend at the current UKRI rate, home rate tuition fees, research expenses and support for training and career enhancement.

Mode of study: Full-time 

Start date:  October 2024

Application deadline: 29 February 2024

Reference number:  MM4L26

Project description

This multidisciplinary project combines biology, physics, engineering, and mathematics to determine how signalling molecules regulate tissue morphogenesis and patterning.

Biological tissues often assume complex shapes and spatial cellular architecture. Recent studies show that tissue architecture plays a role in the dispersal of signalling molecules in developing tissues. Thus, material properties of developing tissues impact the function of biochemical signals.

In this project we will combine tissue engineering (Elosegui-Artola Lab) with theoretical modelling (Hadjivasiliou lab) to address how tissue and cell architecture affect the formation of signalling gradients in tissues.

The student will build on theoretical tools developed in the Hadjivasiliou lab to make predictions about how cell size and packing impacts the shape and range of morphogen gradients in 2D epithelia and in tissues that undergo 3D morphogenetics movements like invagination. The student will learn how to perform reaction-diffusion simulations coupled with algorithms that follow individual cell shape and size. The student will use cells that are synthetically engineered to secrete GFP to test and challenge the predictions of the theoretical model. This will involve growing spherical organoids using GFP secreting cells and engineering 3D micropattern matrices to control the size and shape of the organoids. Live microscopy and quantitative assays such as FRAP (Fluorescence Recovery After Photobleaching) will be applied to organoids of varying size and morphologies to analyse i) how local cell area is coupled to tissue curvature and ii) how molecular dispersal is impacted by cell and tissue morphology.

References

Romanova-Michaelides M, Hadjivasiliou Z, Aguilar-Hidalgo D, Basagiannis D, Seum C, Dubois M, Julicher F, Gonzalez-Gaitan M. Morphogen gradient scaling by recycling of intracellular Dpp.  Nature, 602, 287-293 (2022)

Hadjivasiliou Z, Moore RE, McIntosh R, Galea GL, Clarke JDW, Alexandre P. Basal protrusions mediate spatiotemporal patterns of spinal neuron differentiation. Developmental Cell.  49, 6, 907-919 (2019)

Hadjivasiliou Z, Hunter G. Talking to your neighbors across scales: Long-distance Notch signaling during patterning. Current Topics in Developmental Biology. 150, 299-234, (2022)

 A Elosegui-Artola, A Gupta, A Najibi, BR Seo, R Garry, CM Tringides, I de Lázaro, M Darnell, W Gu, Q Zhou, DA Weitz, L Mahadevan, DJ Mooney. Matrix viscoelasticity controls spatiotemporal tissue organization. Nature Materials. 22,117–127 (2023).

A Elosegui-Artola, I Andreu, A Beedle, A Lezamiz, M Uroz, A Kosmalska, R Oria, JZ Kechagia, P Rico, AL Le Roux, CM Shanahan, X Trepat, D Navajas, S Garcia-Manyes, P Roca-Cusachs. Force triggers YAP nuclear entry by mechanically regulating transport across nuclear pores. Cell. 171, 6, p1397–1410. (2017).

A Elosegui-Artola, R Oria, Y Chen, A Kosmalska, C Pérez-González, N Castro, C Zhu, X Trepat, P Roca-Cusachs. Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity. Nature Cell Biology. 18, pp 540–548. (2016)

Person specification

• Have a first degree in Biophysics, Biology, Biomaterials or another related area. 
• Good communication skills, both written and oral, including the ability to write for publication, present research proposals and results.
• Interest in interdisciplinary research.

Research training

You will gain interdisciplinary skills in biophysics, quantitative methods development, theoretical biology, materials engineering and synthetic biology.

Next steps and contact for further information

Please contact Dr Alberto Elosegui-Artola at alberto.eloseguiartola@crick.ac.uk

To view entry requirements, further general information and how to apply, see the main page for the Multiscale Models for Life (MM4L) Centre for Doctoral Training